종양 괴사 인자-알파 에 대한 특이적 결합 친화성을 갖는 소분자 화합물의 발견
Identification of a Small Molecule Compound with Targeted Binding Affinity to Tumor Necrosis Factor-Alpha
- 주제(키워드) Tumor necrosis factor-alpha
- 주제(DDC) 547
- 발행기관 아주대학교 일반대학원
- 지도교수 Sangdun Choi
- 발행년도 2024
- 학위수여년월 2024. 2
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000033357
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Tumor Necrosis Factor-alpha (TNF-α), a pro-inflammatory cytokine, is associated with the pathogenesis of diverse injuries. Medications targeting the dysregulated TNF-α in the body have been extensively used. However, most TNF-α inhibitors are monoclonal antibodies, presenting diverse side effects and limitations. This research employed computer-based analysis to design a TNF-α inhibitor as a small-molecule compound and demonstrated it through related experiments. When TNFR binds to TNF-α, trimerization occurs, leading to downstream activation, resulting in cellular inflammatory responses or cell death. Our study commenced with a focus on inhibiting the formation of these TNF-α trimers, aiming to improve the uncontrolled functionality of TNF-α. Our designed compound aimed to bind within the TNF-α trimer's pocket, a validation supported by docking tests conducted with the MOE interface and confirmed through SPR analysis. Additionally, we demonstrated that this compound inhibits TNF-α inflammatory signaling in cell-based experiments. Considering its notably low cytotoxicity, there is potential for it to act significantly as a TNF-α inhibitor within the body. Moreover, through structural analysis of the lead compound, we identified residues that seem to exhibit a meaningful impact as TNF-α inhibitors. These findings suggest new prospects for our research in both the small molecule compound market and pathological investigations. Keywords : Tumor Necrosis Factor-alpha, Small molecule compound inhibitor, Trimerization, docking, SEAP assay
more목차
INTRODUTION 1
RESULTS 3
Design process of TNF-α inhibitors as small molecule compound 3
TTA08 exhibits potential as TNF-α inhibitor in cell experiments and binding affinity test 3
TTA08 effectively inhibits TNF-α-induced NF-κB signaling 5
Specific binding of TTA08 with TNF-α was demonstrated through docking simulation and SPR analysis 6
DISCUSSION 16
MATERALS & METHODS 19
Chemical Library Preparation 19
2D fingerprint search 19
Pharmacophore modeling 20
Pharmacophore-based virtual screening 20
Docking 20
Toxicity check 21
Cells and reagents 21
SEAP activity assay 21
Cell survival assay 22
Surface plasmon resonance (SPR) analysis 22
Western blot analysis 23
REFERENCES 24
